Trained immunity in the retina and its influence on retinal degenerative disorders

• Applicant: Professor Dr. Thomas Langmann
• Subject Area: Ophthalmology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 459037870

We and others have previously demonstrated that when retinal microglia and macrophages become pathologically activated through sustained stimulation, they release inflammatory mediators that are harmful to retinal cells, thereby contributing to retinal degenerative diseases and vision loss. Our work during the first funding period unequivocally established that innate immune memory, also known as immune training, is present in the degenerating retina. Specifically, we revealed that a history of systemic inflammation exacerbates retinal degeneration by inducing pronounced metabolic and epigenetic reprogramming in retinal immune cells. The proposed study aims to address two specific objectives: Aim 1: To validate our findings on retinal immune training induced by metabolic and microbial stimuli using independent in vivo models of retinal injury. This will demonstrate that immune training is a universal phenomenon playing a critical role in retinal diseases. Aim 2: To evaluate whether disrupting immune memory through cell-specific knockout of transforming growth factor-activated kinase 1 (Tak1), a key regulator of innate immunity, can improve disease outcomes in two mouse models of retinal pathology. This study will shed light on the mechanisms underlying immune cell activation in the retina and investigate the interactions between prolonged environmental stress exposure and the progression of retinal diseases. Crucially, successful completion of this work is expected to identify pivotal mediators of trained immunity in the retina, paving the way for novel therapeutic strategies to combat retinal pathologies.

• DFG Programme: Research Grants
• International Connection: Canada, United Kingdom
• Cooperation Partners: Professor Dr. Andrew Dick; Professor Przemyslaw Mike Sapieha, Ph.D.